Oligodendrocyte dysfunction in schizophrenia and bipolar disorder

Tkachev, Dmitri; Mimmack, Michael L.; Ryan, Margaret M.; Wayland, Matthew T.; Freeman, Tom P; Jones, Peter B.; Starkey, Mike; Webster, Maree J.; Yolken, Robert H.; Bahn, Sabine

doi:10.1016/s0140-6736(03)14289-4

Cited by 858 publications

(676 citation statements)

References 36 publications

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“…These genes include 2 0 -3 0 -cyclic nucleotide 3 0 -phosphodiesterase (CNP), V-ERB-B2 avian erythroblastic leukemia viral oncogene homologue 3 (ERBB3), gelsolin (GSN), myelin and lymphocyte protein (MAL), myelin-associated glycoprotein (MAG), myelin and lymphocyte protein (MLP) and transferin (TF). [14][15][16][17][18] (3) Myelination of the prefrontal cortex typically peaks in late adolescence and early adulthood, thus coinciding with the onset of symptoms of schizophrenia. Moreover, schizophrenia patients manifest symptoms similar to those observed in nonschizophrenia patients with prefrontal demyelination.…”

Section: Introductionmentioning

confidence: 99%

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

et al. 2007

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Several lines of evidence, including expression analyses, brain imaging and genetic studies suggest that the integrity of myelin is disturbed in schizophrenia patients. In this study, we first reconstructed a pathway of 138 myelin-related genes, all involved in myelin structure, composition, development or maintenance. Then we performed a two-stage association analysis on these 138 genes using 771 single nucleotide polymorphisms (SNPs). Analysis of our data from 310 cases vs 880 controls demonstrated association of 10 SNPs from six genes. Specifically, we observed highly significant P-values for association in PIK4CA (observed P = 6.1 Â 10 À6 ). These findings remained significant after Bonferroni correction for 771 tests. The PIK4CA gene is located in the chromosome 22q11 deletion syndrome region, which is of particular interest because it has been implicated in schizophrenia. We also report weak association of SNPs in PIK3C2G, FGF1, FGFR1, ARHGEF10 and PSAP (observed Pp0.01). Our approach-of screening genes involved in a particular pathway for association-resulted in identification of several, mostly novel, genes associated with the risk of developing schizophrenia in the Dutch population.

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Section: Introductionmentioning

confidence: 99%

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

et al. 2007

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“…[12][13][14] There is now emerging evidence that the gene for ERBB4 also influences risk for schizophrenia, 15,16 especially when considered together with NRG1. 16 Moreover, there is evidence from postmortem mRNA studies for alterations in the levels of ERBB4 15 (as well as the ERBB3 coreceptor [17][18][19][20][21] ) in schizophrenia. A recent study that investigated neuregulin stimulation of ERBB4 in slices of prefrontal cortex from control and schizophrenic subjects demonstrated enhanced activation of ERBB4 by neuregulin in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

et al. 2007

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Neuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase b/f (RPTPb), we postulated that simultaneous binding of MAGI proteins to RPTPb and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPb. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPb for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n = B1400). PTPRZ1, which codes for RPTPb, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P = 0.0003; gene-wide P = 0.0064; hypothesiswide P = 0.026). The data provide evidence for a role of PTPRZ1, and for RPTPb signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPb in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia.

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“…Dysregulation of several of these genes inhibited oligodendrocyte development and function. Similarly, Tkachev et al 9 also demonstrated that many myelinrelated genes were downregulated except that MPZL1/PZR was significantly upregulated in schizophrenia (1.29-fold, P = 0.0263). Myelin synthesis by oligodendrocytes, which also plays an important part in axonal survival, provides the basis for rapid impulse conduction in CNS.…”

Section: Discussionmentioning

confidence: 73%

“…7 It showed lower expression only in the brain whereas exhibiting upregulation in all the other tissues tested including the heart, placenta, kidney and pancreas. 8 Recently, Tkachev et al 9 reported abnormal expression of the myelin-related genes in the study of schizophrenia and bipolar disorder. Most myelinrelated genes, such as MBP, MAG, MOBP, PLP1 and MOG, were downregulated, whereas MPZL1/PZR was significantly upregulated in schizophrenia as compared to normal controls (1.29-fold, P = 0.0263).…”

Section: Introductionmentioning

confidence: 99%

“…This result was in agreement with the results from a parallel quantitative-polymerase chain reaction (PCR) study. 9 The aim of this study was to test MPZL1/PZR as a possible novel gene associated with schizophrenia. We selected 523 Han Chinese trios giving consideration to population stratification and issues of detection for power of association.…”

Section: Introductionmentioning

confidence: 99%

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MPZL1/PZR, a novel candidate predisposing schizophrenia in Han Chinese

Liu

Qin

et al. 2006

Mol Psychiatry

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The MPZL1/PZR gene has been mapped to 1q23.3, located in close proximity to a recognized schizophrenia susceptibility locus. Recently, the MPZL1/PZR gene has been found to be significantly upregulated in schizophrenia brain tissue and to play an important role in cell signaling, thus indicating that MPZL1/PZR could be a potential schizophrenia marker. To test this hypothesis, we selected three single nucleotide polymorphisms (SNPs) for genotyping in 523 Han Chinese trios. We found that two individual SNPs were significant at the Bonferroni's corrected significance level P < 0.017: rs3767444 (v 2 = 6.299, P = 0.0121) and rs2051656 (v 2 = 9.856, P = 0.0017). Haplotype transmission/disequilibrium tests revealed a significant association with the disease (global P-value = 1.064 Â 10 À6 ), but no specific transmission distortions. Thus, we propose that the MPZL1/PZR gene may be important in the predisposition to schizophrenia among Han Chinese.

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Oligodendrocyte dysfunction in schizophrenia and bipolar disorder

Cited by 858 publications

References 36 publications

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

MPZL1/PZR, a novel candidate predisposing schizophrenia in Han Chinese

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